Familial Hypertrophic cardiomyopathy (FHC) is a genetic cardiac disease with varying symptoms and morphological manifestations which can include sudden death, hemodynamic dysfunction, variable degrees of hypertrophy, and cellular disarray. Although its primary cause is mutations in sarcomeric proteins, multiple factors contribute to the clinical heterogeneity of FHC and its varied phenotypes. Mitochondria, which can undergo respiration, are a likely factor contributing to the disease phenotype. Numerous mutations in mitochondrial DNA (mtDNA) have been detected in cardiomyopathies, including mtDNA-encoded subunits of NADH-ubiquinone oxidoreductase (Complex 1). Specific mutations in mtDNA-coded Complex I subunits can cause a reduction in enzymatic activity. This could lead to an increase in free radical mediated damage given that Complex I inhibition results in an elevation in the rate of free radical production, in vitro. Therefore it is hypothesized that: Mitochondrial respiratory dysfunction contributes to the pathogenesis of FHC. In addition. Mutations in mtDNA encoded subunits of Complex may contribute to decreased enzyme activity. And increased free radical damage to specific cellular components in hearts isolated from FHC. To test these hypotheses, we will use transgenic mouse models of FHC made in the sponsor's laboratory which express mutant cardiac sarcomeric proteins to investigate the role of mitochondrial dysfunction and free radical damage in the pathogenesis of FHC. Preliminary experiments provided in this proposal give evidence of mitochondrial dysfunction and specific declines in Complex I activity in transgenic mouse models of FHC and provide a basis for future experiments examining the role of mitochondrial dysfunction in the pathogenesis of FHC.